Vancomycin and Metronidazole for the Treatment of Clostridium difficile--Associated Diarrhea

To the Editor—We would like to congratulate Zar et al. [1] on their well-designed study, which compared vancomycin with metronidazole in a prospective, randomized, double-blind, placebo-controlled trial as first-line treatment for Clostridium difficile–associated diarrhea (CDAD). They found vancomycin to be superior to metronidazole for the treatment of severe CDAD. As the authors outline, these findings are of tremendous significance, especially in this era of increasing prevalence of the hypervirulent epidemic strain of C. difficile, North American PFGE type 1, ribotype 027, in Canada, the United States, and many parts of Europe [2]. This strain has been associated with increased disease severity and with an increased relapse rate following metronidazole therapy. The use of vancomycin as first-line therapy for CDAD has been discouraged for many years, mainly because of its potential to increase the prevalence of vancomycin-resistant enterococcus (VRE), but also because of its direct cost. Several studies have implicated parenteral and oral vancomycin therapy as a risk factor for VRE acquisition [3–7], whereas others found no correlation between oral vancomycin therapy for C. difficile infection and the development of VRE colonization [8]. Unfortunately, Zar et al. [1] did not evaluate VRE fecal colonization and/or carriage in their patients. Moreover, neither direct complications (such as the development of toxic megacolon and the need for colectomy) nor mortality were compared between groups. Mortality rates reported recently for patients with severe CDAD range from 9% to 25%; more than one-half of these deaths are related to C. difficile infection [9–11]. Comparison between treatment regimens cannot disregard deaths when the disease in question is associated with such a high mortality rate. VRE has become a significant nosocomial pathogen in many hospitals in the United States, as well as in many other developed countries worldwide [12]. Accepting the conclusions proposed by Zar et al. [1] (namely, that vancomycin is superior to metronidazole in treating severe CDAD) will surely result—given the recent increase in the incidence of severe CDAD—in increased treatment with oral vancomycin in hospitals; in turn, this could possibly result in a subsequent increased prevalence of VRE colonization and infection. Do the findings of Zar et al. [1] make vancomycin the first-line treatment for CDAD? Not yet. The findings of this new trial must be evaluated in light of previous evidence [1, 13, 14]. The evidence to date does not show significant superiority of vancomycin over metronidazole; the combined relative risk for cure is 0.93 (95% CI, 0.80–1.09) (figure 1). We believe that further well-designed studies comparing vancomycin with metronidazole are warranted. Additional important outcome variables, such as mortality and ecological impact, must be evaluated. In the meantime, metronidazole should be considered to be first-line treatment for the majority of CDAD cases. Overall symptomatic cure at end of follow-up in randomized, controlled trials comparing metronidazole with vancomycin. Overall symptomatic cure was defined as cure without relapse during the follow-up period. Intention-to-treat analysis was used when possible (with excluded patients being counted as not having been cured), using the random effects model. RR, realtive risk. Potential conflicts of interest.All authors: no conflicts.